Much progress has been made in the last 30 years to improve survival of children with CHD, but what was once a fatal condition is now a manageable long-term disease. Of these, children with Hypoplastic Left Heart Syndrome face the worst outcomes as they are left with a single ventricle (the right ventricle) that ultimately fails. These children are either left with long-term morbidity such as poor exercise tolerance, decreased executive function, and poor social skills. At the worst, they are placed on the transplant list where short-term survival in the highest need cohort is 50%, and grafts have a maximal longevity of roughly 12 years before needing a new heart. The goal of this study is to provide FDA-enabling data for a combination therapy of two Phase 1 FDA approved treatments; cardiac progenitor cells and decellularized porcine cardiac extracellular matrix. Cell therapy is promising in children, but similar to adult studies the cells do not persist for long and are transplanted to a diseased microenvironment. In 3 separate aims, we will examine the efficacy of this combined therapy in both immunocompromised and immune-competent rats, followed by large animal pig studies. These data will not only provide critical data for an FDA IND, but will also shed light on potential physiological mechanisms by which these therapies act. With congenital heart disease occurring in nearly 1% of all births and representing the most common birth defect, the potential impact of this study cannot be understated. Information gleaned from this study will not only improve the lives of nearly 40,000 children per year and their families, but it would also generate greater societal impact in terms of economic and educational outcomes. With both individual therapies under early clinical trials in humans, this proposal is the next logical step toward enhancing pediatric cell therapy.